This K24 renewal application for Molecular Genetics of Melanoma is an expansion of the candidate's previous K24 grant with greater scientific and mentorship investment in patient risk prediction through Next Generation sequencing and in the rapidly growing area of molecular therapeutics. The first five years of this K24 was instrumental in providing the candidate protected time to train investigators in patient-oriented research. The results of his research led to the first Bayes-Mendel risk prediction model in melanoma (MelaPRO) and the description of novel MITF and BAP1 mutations in melanoma-prone families. The candidate was able to mentor 19 individuals, publish 52 manuscripts and successfully compete for over $2.8 million in peer-reviewed grants. Since the initial K24 award in 2010, massive parallel sequencing technologies have become commonplace and genomic medicine is being deployed at the patient's bedside. This K24 renewal proposes to exploit the power of precision medicine to more comprehensively profile melanoma risk and to capitalize on newly-discovered molecular drivers to improve melanoma therapeutics. The scientific expansion builds upon the candidate's long-time experience with patient- oriented genetics investigation and affords him the opportunity to mentor trainees in new areas of interdisciplinary research. The tightly-woven multidisciplinary collaborations which already exist between the candidate and investigators at the MGH Analytic Translational Genetics Unit/Broad Institute and the MGH Cancer Center/Henri and Belinda Termeer Center for Targeted Therapies will allow for (i) new opportunities to mentor and recruit trainees in unrelated fields into patient-oriented research, (i) access to patients and patient-derived material for analysis, (iii) well-defined infrastructures to carry out the proposed studies and (iv) new areas of funding not currently in the candidate's portfolio. This award will also enable the candidate to develop new areas of expertise, to codify new approaches to mentorship and to take on new directions in patient-oriented research.